Biology subjects

Eisemann, T.

Publications and source records attributed to Eisemann, T..

7 recordsLinked to original sources

bioRxiv2025

Interferon Restores Antigen Presentation and Sensitizes Medulloblastoma to T Cell Killing

Medulloblastomas are commonly considered immunologically cold and refractory to immunotherapy. One contributing factor to their low immunogenicity is impaired antigen presentation, which allows tumor cells to escape from cytotoxic T cells. Here we use a syngeneic mouse model of medulloblastoma to study the role of CD8+ T cells in medulloblastoma growth. We demonstrate that despite low expression of MHC Class I on tumor cells, depletion of CD8+ T cells accelerates tumor growth, whereas adoptive transfer of tumor-reactive CD8+ T cells prolongs survival. These anti-tumor effects rely on T cells secreting interferon gamma (IFN{gamma}), which induces MHC class I on tumor cells and facilitates tumor cell killing by T cells. Notably, this response is essential for CD8+ T cell-mediated tumor attack, as blocking IFN{gamma} signaling in vivo abrogates MHC class I induction and eliminates the beneficial effect of T cells. Importantly, delivering IFN{gamma} directly into tumors via convection-enhanced delivery (CED) enhances CD8+ T cell-mediated killing of tumor cells and significantly prolongs survival in tumor-bearing mice. These studies highlight the importance of T cells in controlling brain tumor growth and the value of IFN{gamma} as an adjuvant for T cell-based immunotherapy.

cancer biology↗

bioRxiv2025

CD155 regulates tumor growth and immune evasion in diffuse midline glioma.

Diffuse midline glioma (DMG) is a devastating pediatric brain tumor with an unmet need for novel therapies. Immune checkpoint inhibitors have failed to prolong survival for DMG patients. In this study, we analyzed the expression of immune checkpoint molecules in human and murine DMG cells, as well as primary brain tumor samples, and identified CD155 as the most highly expressed. When murine DMG cells were co-cultured with CD8+ T cells, silencing of CD155 led to a marked increase in T cell-mediated killing. Strikingly, CD155-deficient DMG cells failed to grow in immunocompetent mice, and depletion of CD8+ T cells allowed these tumors to grow. CD155 also exerted cell-autonomous effects on tumor cells: silencing of CD155 led to induction of apoptosis of DMG cells and to delayed tumor growth in immunodeficient mice. Transcriptomic analyses identified FOXM1 as a key target of CD155. Notably, FOXM1 silencing also led to reduced proliferation of DMG cells in vitro and in vivo. Finally, treatment of DMG-bearing mice with Thiostrepton, a FOXM1-targeting agent, delayed tumor growth and prolonged survival. These studies demonstrate that CD155 regulates immune evasion and tumor growth in DMG, and suggest that targeting CD155 could be a valuable two-pronged therapeutic strategy for this disease. Conflict-of-interest statementThe authors have declared that no conflict of interest exists.

cancer biology↗

bioRxiv2025

Synergistic RAS-MAPK and AKT Activation in MYC-Driven Tumors via Adjacent PVT1 Rearrangements

MYC-driven (MYC+) cancers are aggressive and often fatal. MYC dysregulation is a key event in these cancers, but overexpression of MYC alone is not always enough to cause cancer. Plasmocytoma Variant Translocation 1 (PVT1), a long non-coding RNA (lncRNA) adjacent to MYC on chromosome 8 is a rearrangement hotspot in many MYC+ cancers. In addition to being co-amplified with MYC, the genomic rearrangement at PVT1 involves translocation, which has had obscure functional consequences. We report that translocation at the PVT1 locus cause asymmetric enrichment of 5-PVT1 and loss of 3-PVT1. Despite being classified as a non-coding RNA, the retained 5 region of PVT1 generates a circular RNA (CircPVT1) that codes for the novel peptide we call Firefox (FFX). FFX augments AKT signaling and synergistically activates MYC and mTORC1 in these cells. Further, the 3 end of PVT1, which is lost during the translocation, codes for a tumor-suppressing micropeptide we named as Honeybadger (HNB). We demonstrate that HNB interacts with KRAS and disrupts the activation of KRAS effectors. Loss of HNB leads to activation of RAS/MAPK signaling pathway, and enhances MYC stability by promoting phosphorylation of MYC at Ser62. These findings identify PVT1 as a critical node that synchronizes MYC, AKT, and RAS-MAPK activities in cancer. Our study thus identifies a key mechanism by which rearrangements at the PVT1 locus activate additional oncogenic pathways that synergize with MYC to exacerbate the aggressiveness of MYC+ cancers. This newfound understanding explains the poor prognosis associated with MYC+ cancers and offers potential therapeutic targets that could be leveraged in treatment strategies for these cancers.

cancer biology↗

bioRxiv2021

Tankyrase interacts with the allosteric site of glucokinase and inhibits its glucose-sensing function in the beta cell

Insulin secretion in the pancreatic beta cell is rate-limited by glucokinase (GCK), the glucose sensor that catalyzes the first step of glucose metabolism. GCK consists of two lobes connected by a flexible hinge that allows the kinase to exhibit a spectrum of conformations ranging from the active, closed form to several inactive, less-compact forms. Activating GCK mutations can cause hyperinsulinemia and hypoglycemia in infants. A similar phenotype exhibited by tankyrase (TNKS)-deficient mice prompted us to investigate whether TNKS might modulate the glucose-sensing function of GCK. We found that TNKS colocalizes and directly interacts with GCK. Their interaction is mediated by two ankyrin-repeat clusters (ARC-2 and -5) in TNKS and a tankyrase-binding motif (TBM, aa 63-68) in the GCK hinge. This interaction is conformation sensitive, human GCK variants that cause hyperglycemia (V62M) or hypoglycemia (S64Y) enhance or diminish the interaction respectively, even though they have no impact on TNKS interaction in the context of a GCK peptide (V62M) or a peptide library (S64Y). Moreover, the TNKS-GCK interaction is inhibited by high glucose concentrations, which are known to stabilize GCK in the active (closed, glucose-avid) conformation. Conversely, glucose phosphorylation by GCK in vitro is inhibited by TNKS. To study this in vitro inhibitory effect in the MIN6 beta cells, we showed that glucose-stimulated insulin secretion is suppressed upon stabilization of the TNKS protein and is conversely enhanced upon TNKS knockdown. Based on these findings as well as by contrasting with hexokinase-2, we propose that TNKS is a physiological GCK inhibitor in pancreatic beta cells that acts by trapping the kinase in the open (inactive) conformation.

cell biology↗

bioRxiv2020

The Sec1/Munc18 protein Vps45 holds the Qa-SNARE Tlg2 in an open conformation

ABSTRACTFusion of intracellular trafficking vesicles is mediated by the assembly of soluble N-ethylmaleimide-sensitive fusion protein receptors (SNAREs) to form membrane-bridging complexes. Also required for SNARE-mediated membrane fusion are Sec1/Munc18-family (SM) proteins, SNARE chaperones that can function as templates to catalyze SNARE complex assembly. In the paradigmatic structure of an SM–SNARE complex, Munc18-1 bound to the Qa-SNARE syntaxin 1, the SNARE protein is trapped in an autoinhibited closed conformation that prevents it from entering into SNARE complexes. Here, we present the structure of a second SM–Qa-SNARE complex, Vps45–Tlg2. Strikingly, Vps45 holds Tlg2 in an open conformation, with its SNARE motif disengaged from its three-helical Habc domain and its linker region unfolded. The domain 3a helical hairpin of Vps45 is unfurled, exposing the presumptive R-SNARE binding site to allow template complex formation. Tlg2 has a pronounced tendency to self-associate via its SNARE motif, and we demonstrate that Vps45 can rescue Tlg2 oligomers into stoichiometric Vps45–Tlg2 complexes. Our findings demonstrate that SM proteins can engage Qa-SNAREs using at least two different modes, one in which the SNARE is closed and one in which it is open.Competing Interest StatementThe authors have declared no competing interest.View Full Text

cell biology↗

bioRxiv2020

A novel neural stem cell-derived immunocompetent mouse model of glioblastoma for preclinical studies

Glioblastomas are the most lethal tumors affecting the central nervous system in adults. Simple and inexpensive syngeneic in vivo models that closely mirror human glioblastoma, including interactions between tumor and immune cells, are urgently needed for deciphering glioma biology and developing more effective treatments. Here, we generated glioblastoma cell lines by repeated in-vivo passaging of cells isolated from a neural stem cell-specific Pten/p53 double-knockout genetic mouse brain tumor model. Transcriptome and genome analyses of the cell lines revealed molecular heterogeneity comparable to that observed in human glioblastoma. Upon orthotopic transplantation into syngeneic hosts they formed high-grade gliomas that faithfully recapitulated the histopathological features, invasiveness and myeloid cell infiltration characteristic of human glioblastoma. These features make our cell lines unique and useful tools to study multiple aspects of glioblastoma pathomechanism and test novel treatments, especially immunotherapies in syngeneic preclinical models.

cancer biology↗

bioRxiv2019

Modeling glioblastoma invasion using human brain organoids and single-cell transcriptomics

Glioblastoma multiforme (GBM) are devastating neoplasms with high invasive capacity. GBM has been difficult to study in vitro. Therapeutic progress is also limited by cellular heterogeneity within and between tumors. To address these challenges, we present an experimental model using human cerebral organoids as a scaffold for patient-derived glioblastoma cell invasion. By tissue clearing and confocal microscopy, we show that tumor cells within organoids extend a network of long microtubes, recapitulating the in vivo behavior of GBM. Single-cell RNA-seq of GBM cells before and after co-culture with organoid cells reveals transcriptional changes implicated in the invasion process that are coherent across patient samples, indicating that GBM cells reactively upregulate genes required for their dispersion. Functional therapeutic targets are identified by an in silico receptor-ligand pairing screen detecting potential interactions between GBM and organoid cells. Taken together, our model has proven useful for studying GBM invasion and transcriptional heterogeneity in vitro, with applications for both pharmacological screens and patient-specific treatment selection at a time scale amenable to clinical practice.

cancer biology↗